Johri Ashu, Yadav Sanjay, Dhawan Alok, Parmar Devendra
Developmental Toxicology Division, Indian Institute of Toxicology Research (Formerly Industrial Toxicology Research Centre), P. O. Box 80, M. G. Marg, Lucknow-226 001, India.
Toxicol Appl Pharmacol. 2008 Aug 15;231(1):10-6. doi: 10.1016/j.taap.2008.03.019. Epub 2008 Apr 8.
Prenatal exposure to low doses of lindane has been shown to affect the ontogeny of xenobiotic metabolizing cytochrome P450s (CYPs), involved in the metabolism and neurobehavioral toxicity of lindane. Attempts were made in the present study to investigate the responsiveness of CYPs in offspring prenatally exposed to lindane (0.25 mg/kg b. wt.; 1/350th of LD(50); p. o. to mother) when challenged with 3-methylcholanthrene (MC) or phenobarbital (PB), inducers of CYP1A and 2B families or a sub-convulsant dose of lindane (30 mg/kg b. wt., p. o.) later in life. Prenatal exposure to lindane was found to produce an increase in the mRNA and protein expression of CYP1A1, 1A2, 2B1, 2B2 isoforms in brain and liver of the offspring at postnatal day 50. The increased expression of the CYPs in the offspring suggests the sensitivity of the CYPs during postnatal development, possibly, to low levels of lindane, which may partition into mother's milk. A higher increase in expression of CYP1A and 2B isoenzymes and their catalytic activity was observed in animals pretreated prenatally with lindane and challenged with MC (30 mg/kg, i. p. x 5 days) or PB (80 mg/kg, i. p. x 5 days) when young at age (approx. 7 weeks) compared to animals exposed to MC or PB alone. Further, challenge of the control and prenatally exposed offspring with a single sub-convulsant dose of lindane resulted in an earlier onset and increased incidence of convulsions in the offspring prenatally exposed to lindane have demonstrated sensitivity of the CYPs in the prenatally exposed offspring. Our data assume significance as the subtle changes in the expression profiles of hepatic and cerebral CYPs in rat offspring during postnatal development could modify the adult response to a later exposure to xenobiotics.
已有研究表明，产前暴露于低剂量林丹会影响参与林丹代谢及神经行为毒性的外源性物质代谢细胞色素P450（CYP）的个体发育。本研究旨在探究产前暴露于林丹（0.25 mg/kg体重；半数致死量的1/350；经口给予母体）的后代，在其成年后受到3-甲基胆蒽（MC）或苯巴比妥（PB）（CYP1A和2B家族的诱导剂）或亚惊厥剂量的林丹（30 mg/kg体重，经口）刺激时，CYP的反应性。结果发现，产前暴露于林丹会使后代出生后第50天时脑和肝中CYP1A1、1A2、2B1、2B2亚型的mRNA和蛋白表达增加。后代中CYP表达的增加表明，产后发育期间CYP可能对低水平的林丹敏感，而林丹可能会进入母乳中。与单独暴露于MC或PB的动物相比，产前经林丹预处理并在幼年（约7周龄）时受到MC（30 mg/kg，腹腔注射×5天）或PB（80 mg/kg，腹腔注射×5天）刺激的动物，其CYP1A和2B同工酶的表达及催化活性增加更为明显。此外，用单次亚惊厥剂量的林丹刺激对照及产前暴露的后代，结果显示产前暴露于林丹的后代惊厥发作更早且发生率更高，这表明产前暴露的后代中CYP具有敏感性。我们的数据具有重要意义，因为大鼠后代出生后发育期间肝脏和大脑中CYP表达谱的细微变化可能会改变成年后对外源性物质后续暴露的反应。
